Chronic Nitric Oxide Synthase Inhibition Prevents New Coronary Capillary Generation

Abstract

L-NAME-induced hypertension has been shown to produce concentric (eutrophic) remodeling of the heart despite an enhanced afterload. We postulated that nitric oxide synthase inhibition could limit coronary capillary growth to explain the nature of remodeling. To test our hypothesis, we aimed at determining the effect of endogenous and exogenous nitric oxide on coronary neovascularization. Aortic and coronary rings from normotensive animals were incubated in a three-dimensional type I collagen matrix in the presence of L-NAME or the nitric oxide donor SNAP. L-NAME inhibited, while SNAP stimulated, neovascularization from aortic and coronary rings after 12 days of in vitro incubation. In arterial rings harvested from rats treated with L-NAME for 14 days and in which no further in vitro treatment was added, only coronary rings showed a reduction in new capillary generation. While confirming that chronic L-NAME-treated rats develop concentric remodeling, the evaluation of capillary density did not reveal any difference as compared with the controls in 3 areas of the myocardium. In conclusion, chronic inhibition of nitric oxide synthesis in vivo produces a long-lasting reduction in the capacity of coronary arteries to generate new capillaries in vitro. Thus, our results lend support to the hypothesis that an inhibition of new capillary formation could prevent the development of compensatory ventricular hypertrophy, in favor of concentric remodeling.

Renin inhibition mitigates anti-angiogenesis in spontaneously hypertensive rats

“…We furthermore introduced during adulthood L-NAME to the drinking water to mimic an advanced cardiovascular burden as L-NAME promotes capillary rarefaction and in second-line aggravates blood pressure development and cardiac remodeling [2,12]. Girardot et al [26] described that L-NAME-induced cardiac remodeling Cardiac morphology. In L-nitro-arginine methyl ester (L-NAME)-treated spontaneously hypertensive rats (SHRs) with vehicle (a) and aliskiren pretreatment (b) Sirius Red staining (40Â magnifications) revealed strong differences in cardiac interstitial collagen deposition as quantified in (e).…”

Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome

“…Given these results, and the recent work of others examining the effects of chronic reductions in nitric oxide bioavailability on microvascular network structure (25,35,40,41), LZR were treated with L-NAME to investigate the effects of low nitric oxide bioavailability per se without the confounding influence of elevated oxidant stress on microvascular structure and function and skeletal muscle perfusion. Chronic inhibition of nitric oxide synthase did not impact any of the systemic measurements in LZR, with the singular exception of mean arterial pressure (abolished by concurrent treatment with hydralazine).…”

“…Taken together, these observations suggest that alterations to microvascular structure could play a major role in limiting skeletal muscle perfusion with increased metabolic demand in OZR. Given the observations that the insulinresistant condition, strongly present in OZR, causes a chronic reduction in the bioavailability of nitric oxide (23,33,53) and that previous studies examining mechanisms of angiogenic collateralization have suggested the central importance of nitric oxide bioavailability in the development of new microvessels (25,35,40,41), we hypothesized that chronic reductions in nitric oxide bioavailability, in part via oxidative radical scavenging (4,58), might contribute to structural alterations to microvascular networks in skeletal muscle of OZR, elevating vascular resistance and impairing functional hyperemic responses.…”

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

“…27 There is ample evidence that MMPs in general, and MMP-2 more specifically, are involved in hypertrophic cardiovascular remodeling (see introduction). We chose MMP-2 as our primary candidate because MMP-2 is expressed at lower transmural pressures in coronary arteries studied ex vivo.…”